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CARDIOVASCULAR

Cyclooxygenase, p38 Mitogen-Activated Protein Kinase (MAPK), Extracellular Signal-Regulated Kinase MAPK, Rho Kinase, and Src Mediate Hydrogen Peroxide-Induced Contraction of Rat Thoracic Aorta and Vena Cava

Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan

In hypertension, blood vessels exhibit increased reactive oxygen species production that may alter vascular tone. We previously observed that H₂O₂ contracted rat thoracic vena cava under resting tone and aorta contracted with KCl. In arteries but not veins, H₂O₂-induced contraction required extracellular Ca²⁺ influx. Because of this difference in Ca²⁺ utilization, we hypothesized that signaling pathways mediating H₂O₂-induced contraction in vena cava under resting tone differed from those mediating H₂O₂-induced contraction in aorta contracted with KCl. Inhibitors of cyclooxygenase (COX) 1 and 2 (indomethacin, 10 µM), thromboxane A₂ (TXA₂) receptors [ICI185282 (2RS,4RS,5SR-4-o-hydroxyphenyl-2-trifluoromethyl-1,3-dioxan-5-yl heptenoic acid), 10 µM], p38 mitogen-activated protein kinase (MAPK) [SB203580 (4-[5-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-1H-imidazol-4-yl]pyridine), 10 µM], extracellular signal-regulated kinase (Erk) [PD98059 (2'-amino-3'-methoxyflavone), 10 µM], src [PP1 (4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, 10 µM], and rho kinase [Y27632 (trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide dihydrochloride), 10 µM], significantly reduced H₂O₂-induced contraction in vena cava under resting tone and aorta after KCl (30 mM) contraction. In contrast, the phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, 20 µM] did not reduce aortic or venous H₂O₂-induced contraction. p38 MAPK, Erk MAPK, and src inhibition did not reduce aortic or venous contraction to the TXA₂ receptor agonist U46619 [GenBank] (9,11-dideoxy-9,11-methanoepoxy PGF₂, 1 µM), whereas rho kinase inhibition significantly reduced aortic and venous contraction to U46619 [GenBank] , and PI3-K inhibition reduced venous contraction to U46619. [GenBank] Our data suggest that, in rat thoracic aorta and vena cava, a COX-derived metabolite is one important mediator of H₂O₂ contraction, possibly via rho kinase activation, and that H₂O₂-induced contraction via p38 and Erk MAPK probably occurs independently of TXA₂ receptor activation.

Address correspondence to: Keshari Thakali, B445 Life Sciences Building, Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317. E-mail: thakalik{at}msu.edu

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